title: Approaches to the synthesis of a novel, anti-HIV active integrase inhibitor.
abstract: The novel HIV-1 integrase inhibitor 1, discovered in our laboratory, exhibits potent anti-HIV activity against a diverse set of HIV-1 isolates and also against HIV-2 and SIV. In addition, this compound displays low cellular cytotoxicity and possesses a favorable in vitro drug interaction profile with respect to isozymes of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT). However, the total synthesis of this significant HIV integrase inhibitor has not been reported. This contribution describes an optimized, reproducible, multi-step, synthetic route to inhibitor 1. The yield for the separate steps averaged about 80%. The methodologies utilized in the synthesis were, among others, a palladium-catalyzed cross-coupling reaction, a crossed-Claisen condensation, and a hydrazino amide synthesis step. Successful alternative synthetic methodologies for some of the steps are also described.
authors.affiliation: Center for Drug Discovery and College of Pharmacy, University of Georgia, Athens, GA 30602, USA. vnair@uga.edu.
authors.forename: Maurice
authors.initials: M
authors.lastname: Okello
authors.forename: Malik
authors.initials: M
authors.lastname: Nishonov
authors.forename: Pankaj
authors.initials: P
authors.lastname: Singh
authors.forename: Sanjay
authors.initials: S
authors.lastname: Mishra
authors.forename: Naveen
authors.initials: N
authors.lastname: Mangu
authors.forename: Byung
authors.initials: B
authors.lastname: Seo
authors.forename: Machhindra
authors.initials: M
authors.lastname: Gund
authors.forename: Vasu
authors.initials: V
authors.lastname: Nair
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D019428:HIV Integrase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D019427:HIV Integrase